rs145110602

Positions:

chrX-14844672-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001018113.3(FANCB):c.1996G>A(p.Gly666Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00084 in 1,208,885 control chromosomes in the GnomAD database, including 7 homozygotes. There are 276 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0032 ( 1 hom., 103 hem., cov: 23)

Exomes 𝑓: 0.00060 ( 6 hom. 173 hem. )

Consequence

FANCB
NM_001018113.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 0.455

Variant links:

Genes affected

FANCB (HGNC:3583): (FA complementation group B) This gene encodes a member of the Fanconi anemia complementation group B. This protein is assembled into a nucleoprotein complex that is involved in the repair of DNA lesions. Mutations in this gene can cause chromosome instability and VACTERL syndrome with hydrocephalus. [provided by RefSeq, Apr 2016]

FANCB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0074588656).

BP6

Variant X-14844672-C-T is Benign according to our data. Variant chrX-14844672-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 246612.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1}. Variant chrX-14844672-C-T is described in Lovd as [Likely_benign]. Variant chrX-14844672-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00317 (353/111523) while in subpopulation AFR AF= 0.0104 (319/30687). AF 95% confidence interval is 0.00946. There are 1 homozygotes in gnomad4. There are 103 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 103 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCB	NM_001018113.3 linkuse as main transcript	c.1996G>A	p.Gly666Ser	missense_variant	9/10	ENST00000650831.1	NP_001018123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCB	ENST00000650831.1 linkuse as main transcript	c.1996G>A	p.Gly666Ser	missense_variant	9/10		NM_001018113.3	ENSP00000498215	P2

Frequencies

GnomAD3 genomes

AF:

0.00311

AC:

347

AN:

111473

Hom.:

Cov.:

AF XY:

0.00291

AC XY:

AN XY:

33725

show subpopulations

Gnomad AFR

AF:

0.0102

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000476

Gnomad ASJ

AF:

0.00719

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000943

Gnomad OTH

AF:

0.00334

GnomAD3 exomes

AF:

0.00116

AC:

212

AN:

183142

Hom.:

AF XY:

0.000856

AC XY:

AN XY:

67780

show subpopulations

Gnomad AFR exome

AF:

0.0109

Gnomad AMR exome

AF:

0.000255

Gnomad ASJ exome

AF:

0.00601

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000159

Gnomad OTH exome

AF:

0.000888

GnomAD4 exome

AF:

0.000604

AC:

663

AN:

1097362

Hom.:

Cov.:

AF XY:

0.000477

AC XY:

173

AN XY:

362772

show subpopulations

Gnomad4 AFR exome

AF:

0.0124

Gnomad4 AMR exome

AF:

0.000455

Gnomad4 ASJ exome

AF:

0.00645

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000370

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000107

Gnomad4 OTH exome

AF:

0.00217

GnomAD4 genome

AF:

0.00317

AC:

353

AN:

111523

Hom.:

Cov.:

AF XY:

0.00305

AC XY:

103

AN XY:

33785

show subpopulations

Gnomad4 AFR

AF:

0.0104

Gnomad4 AMR

AF:

0.000476

Gnomad4 ASJ

AF:

0.00719

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000943

Gnomad4 OTH

AF:

0.00329

Alfa

AF:

0.000649

Hom.:

Bravo

AF:

0.00367

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0112

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.00114

AC:

139

EpiCase

AF:

0.000109

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 19, 2018	- -

History of neurodevelopmental disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 16, 2013

Co-segregation data for this variant is currently unavailable.This variant has not been detected in conjunction with a pathogenic mutation to date.This variant was previously reported in the SNPDatabase as rs145110602. Based on data from the NHLBI Exome Sequencing Project (ESP), the A-allele has an overall frequency of approximately 0.25% (5/1997) total male alleles studied and but was not observed in the homozygous state out of 3381females studied. The A-allele was observed in 0.96% (5/522) African American male alleles but was absent out of 1475 European American male alleles studied. Based on data from the 1000 Genomes Project, the A-allele has an overall frequency of approximately 2/1048 (0.19%) and the highest frequency was in 2/48 (4.17%) African-American SW male chromosomes studied.This amino acid position is not conserved on species alignment.This alteration is predicted to be benign with a score of 0.002 (sensitivity: 0.99; specificity: 0.17)This alteration is predicted to be tolerated with a score of 0.390 (conservation: 2.57) -

Fanconi anemia complementation group B

Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Fanconi anemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

FANCB-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 18, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.78

CADD

Benign

1.9

DANN

Benign

0.40

DEOGEN2

Benign

0.062

T;T;T

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.38

T;.;T

MetaRNN

Benign

0.0075

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.85

L;L;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.20

PROVEAN

Benign

-0.70

N;N;N

REVEL

Benign

0.033

Sift

Benign

0.56

T;T;T

Sift4G

Benign

0.78

T;T;T

Polyphen

0.098

B;B;.

Vest4

0.16

MVP

0.21

MPC

0.10

ClinPred

0.0017

GERP RS

-1.1

Varity_R

0.041

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over